The popular recreational drug of abuse, methamphetamine (METH), has the potential to destroy brain serotonin (5-HT) and dopamine (DA) axon terminals in a variety of experimental animals, including various non-human primate species. Evidence from a single PET study and, more recently, post mortem analyses in chronic METH users indicate that humans are also susceptible to METH-induced 5-HT neurotoxicity. The relative severity of METH-induced 5-HT neurotoxicity versus DA neurotoxicity remains to be determined. Given the important role of brain 5-HT neurons in cognitive function and sleep, it is of significant interest to determine whether brain 5-HT neurotoxicity may play a role in cognitive dysfunction in METH users that has been reported by many investigators, or in sleep abnormalities that we have recently documented in abstinent METH users. The purpose of this project is to determine the relative severity of METH-induced DA and 5-HT neurotoxicity in abstinent METH users, and to fully characterize sleep abnormalities in the same individuals. Secondary aims of this project are to explore the relationship between METH-induced reductions in brain monoaminergic markers and alterations in cognition and sleep in METH users. A better understanding of the long-term neurotoxic effects of METH in humans could lead to additional and improved targeted pharmacotherapeutic approaches for METH abuse and dependence. The three primary aims of this project are: 1) To concomitantly assess the status of brain 5-HT and DA neurons in abstinent METH users by using positron emission tomography (PET) to measure 5-HT transporter (SERT) and DA transporter (DAT) binding potentials (BP) in abstinent METH users and healthy controls employing [11C] DASB and [11C] MPH as radioligands; 2) To obtain and compare sleep polysomnographic measures in these same subject groups and; 3) To obtain and compare formal neuropsychiatric (cognitive) measures in these same subject groups, and explore potential relationships between cognitive performance and PET markers of the SERT and DAT obtained in Aim 1. A fourth, exploratory, aim is: 4) To assess the potential relationships between measures of sleep, cognition, and PET markers of the DAT and SERT in abstinent METH users and controls. The proposed research will be the first to simultaneously evaluate brain markers of 5-HT and DA neurons in abstinent METH users, to obtain formal sleep polysomnographic measures in abstinent METH users, and to explore the relationship of brain markers of the DAT and SERT to cognitive and sleep abnormalities in the same individuals. PUBLIC HEALTH RELEVANCE: The overall goal of the present project is to uses state-of-the-art imaging, polysomnographic and behavioral methods to elucidate the neurobiological and behavioral consequences of methamphetamine (METH) abuse and dependence.